INTRODUCTION — Acute leukemia accounts for approximately 30 percent of all childhood malignancies and is the most common cancer in children. Acute myeloid leukemia (AML) accounts for approximately 15 percent of childhood leukemia and is much less common in the pediatric population than acute lymphoblastic leukemia (ALL), which accounts for 80 percent of pediatric acute leukemia. Survival rates for AML have greatly improved over the past several decades; however, overall survival for children with AML is approximately 65 to 70 percent and remains lower than for children with ALL [1]. The improvements in survival have been achieved through clinical trials investigating the role of intensification of therapy, including the use of allogeneic hematopoietic cell transplantation (HCT), as well as improvements in supportive care.
This topic will provide an overview of AML in children and adolescents, focusing on issues that are of interest to primary care providers. The pathogenesis of AML and discussions of the molecular genetics and cytogenetics in AML are presented separately. Transient myeloproliferative disorder of Down syndrome is also discussed separately. (See "Pathogenesis of acute myeloid leukemia" and "Molecular genetics of acute myeloid leukemia" and "Cytogenetic abnormalities in acute myeloid leukemia" and "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately.
●(See "COVID-19: Considerations in patients with cancer".)
DIAGNOSIS
Clinical presentation — The most common presenting symptoms of AML are reflective of the leukemic burden. Similar to those with acute lymphoblastic leukemia (ALL), patients with AML can present with fever, malaise, musculoskeletal pains, lymphadenopathy, hepatosplenomegaly, and bleeding. A complete blood count most often reveals anemia and thrombocytopenia and can have decreased, normal, or increased white blood cell (WBC) counts with leukemic myeloblasts noted on the peripheral smear. The less common complications described below may require immediate medical intervention.
Disseminated intravascular coagulation (DIC) can be present and can range from mild to severe, especially in some subtypes of AML (eg, acute promyelocytic leukemia). Complications due to the leukemic burden at diagnosis may also include an elevated WBC of >100,000/microL, leading to leukostasis. (See 'Supportive care' below and 'Acute promyelocytic leukemia' below and "Overview of common presenting signs and symptoms of childhood cancer".)
Less often, children may present with symptoms of central nervous system (CNS) involvement (eg, headache, lethargy, mental status changes, cranial nerve palsies) or other extramedullary sites. Significant electrolyte derangements and acute kidney injury can occur, especially in those with high WBC or tumor burden. Hepatic dysfunction can also be present at diagnosis. (See 'Supportive care' below.)
Diagnostic evaluation — In addition to a history and physical examination, it is our practice to perform the following studies in children with suspected AML:
●Laboratory studies – Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, glucose, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, lactate dehydrogenase (LDH), calcium, magnesium, phosphorus, uric acid, albumin and total protein.
●Lumbar puncture – Lumbar puncture for evaluation of the CNS. Cerebrospinal fluid (CSF) should be sent for cell count, protein, glucose, cytology (examination of stained cytospin slides). (See "Lumbar puncture: Indications, contraindications, technique, and complications in children".)
●Bone marrow aspirate and biopsy – Bone marrow examination enables morphologic, immunophenotypic, cytogenetic (ie, karyotype and fluorescence in situ hybridization [FISH]), and molecular testing, which are essential for accurate risk stratification [2]. In some settings, immunophenotypic evaluation by flow cytometry of the peripheral blood can be used for diagnostic purposes, but this does not replace bone marrow evaluation.
●Extramedullary disease – Patients with suspected extramedullary disease should have appropriate radiographic imaging of the suspected sites.
●Screen for familial AML – Screening for familial acute leukemia and myelodysplastic syndromes consists of a careful medical and family history aimed at identifying signs and symptoms of the known familial syndromes. This is discussed in more detail separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Evaluation of patients with AL or MDS'.)
Pathologic features — The pathologic evaluation of suspected AML includes an assessment of blast morphology, immunophenotype, cytogenetics, and molecular features. AML is distinguished from ALL based on the morphology and immunophenotype of the blasts. Findings on metaphase cytogenetics, FISH, and molecular studies are important for risk stratification. Lumbar puncture with CSF analysis is a standard part of the evaluation of children with newly diagnosed AML. The pathologic features of AML are presented in more detail separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Pathologic features'.)
●Morphology – Myeloblasts are immature cells with large nuclei, usually with prominent nucleoli, and a variable amount of pale blue cytoplasm. Typically, myeloid blasts have more abundant cytoplasm compared with lymphoid blasts and may have Auer rods or granules present (picture 1). The morphologic classification of AML has been based upon the French-American-British (FAB) classification that relies on the lineage associated phenotype, ranging from minimally differentiated (FAB M0) to the more mature acute megakaryoblastic leukemia (AMKL, FAB M7). (See "Classification of acute myeloid leukemia (AML)", section on 'AML not otherwise specified'.)
●Immunophenotype – The immunophenotype of the tumor cells can be determined by flow cytometry or by immunohistochemistry. The tumor cell immunophenotype can rapidly distinguish between AML and ALL. It can also determine myeloid-specific lineage but usually does not substitute for morphologic FAB classification. AML expresses numerous markers, including CD11b, CD34, CD33, CD45, CD64, CD65, CD117, myeloperoxidase (MPO), and lysozyme.
●Cytogenetics – Cytogenetic abnormalities can be detected in approximately 75 percent of pediatric AML, and several findings have prognostic or therapeutic implications [3]. Many abnormalities can be detected by conventional karyotype, but some translocations can be cryptic and require FISH or DNA sequencing for detection or confirmation. In addition to conventional karyotyping, FISH should be performed to evaluate for t(8;21), inv(16), t(15;17), and 11q23 translocations. (See "Cytogenetic abnormalities in acute myeloid leukemia" and "Molecular genetics of acute myeloid leukemia".)
●Mutation analysis – Pediatric AML is genetically heterogeneous, the molecular profiles differ from adult AML, and certain mutations or genetic profiles have prognostic or therapeutic implications [4,5]. We suggest mutation analysis with polymerase chain reaction (PCR) and/or next-generation sequencing (NGS). Testing should include NPM1, CEBPA, FLT3/ITD, KIT, and WT1. Comprehensive sequencing that utilizes DNA and RNA sequencing can be utilized to define the genomic profile, including cryptic fusions not detected by conventional cytogenetics [4]. (See "Molecular genetics of acute myeloid leukemia", section on 'Gene mutations'.)
●CSF analysis – The diagnosis of CNS involvement requires either cytologic confirmation of leukemia cells in the CSF, clinical signs of CNS leukemia (eg, facial nerve palsy, brain/eye involvement), or a tumor mass detected by imaging. CNS positivity based on cytology is generally defined as >5 x106/L WBCs in the CSF with the presence of blasts in a non-bloody lumbar puncture.
RISK STRATIFICATION
Overview — Risk stratification in pediatric AML is based on cytogenetic and molecular features, including genomic profiling, and response to induction therapy. While there is general agreement on low-risk cytogenetic features, there is controversy about certain high-risk molecular features because some cooperative groups use different definitions for treatment response.
We suggest use the following risk stratification scheme, which takes into account cytogenetic and molecular features and response to induction chemotherapy:
●Favorable:
•t(8;21)(q22;q22); RUNX1-RUNX1T1
•inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
•Mutated NPM1 without FLT3-ITD (normal karyotype)
•Mutated CEBPA (normal karyotype)
●Intermediate – Cases that do not harbor cytogenetic or molecular abnormalities that classify them as favorable or adverse risk are categorized as intermediate risk. This population is further subclassified based on response to induction therapy. (See 'Response to induction chemotherapy' below.)
●Adverse:
•t(6;9)(p23;q34)/DEK-NUP214
•NUP98-NSD1
•Certain KMT2A rearrangements (see 'High-risk cytogenetics' below)
•CBFA2T3A-GLIS2
•Abnormalities of 3q
•Monosomy 5 or del(5q)
•Monosomy 7
•Complex karyotype
•High allelic ratio FLT3-ITD
•Residual disease following induction therapy (see 'Response to induction chemotherapy' below)
Details regarding the impact of each of these findings are presented in the following sections. There are less data regarding rare subtypes, such as non-Down syndrome acute megakaryoblastic leukemia (AMKL), although results from comprehensive genomic sequencing allows for a more refined risk stratification in this setting [4].
Cytogenetics
Favorable cytogenetics — AML with favorable cytogenetics accounts for approximately 20 to 30 percent of pediatric AML and includes those who harbor the chromosomal abnormalities t(8;21) and inv(16) or t(16;16), also called core binding factor (CBF) AML [5,6]. Treatment on contemporary protocols with chemotherapy alone results in a relapse-free survival rate of approximately 70 percent and an overall survival of approximately 80 percent [6-8]. For patients with non-Down syndrome acute megakaryoblastic leukemia (AMKL), those harboring the RBM15-MKL1 translocation have a more favorable prognosis with an overall survival of approximately 70 percent [4]. (See "Cytogenetic abnormalities in acute myeloid leukemia", section on 't(8;21); RUNX1-RUNX1T1' and "Cytogenetic abnormalities in acute myeloid leukemia", section on 'inv(16) or t(16;16); CBFB-MYH11'.)
The hallmark diagnostic feature of acute promyelocytic leukemia (APL) is the balanced translocation between the PML gene on chromosome 15 and RARA (RAR-alpha) gene on chromosome 17 resulting in the t(15;17)(q22;q21) [9]. Patients with APL can achieve excellent outcomes when treated with appropriate regimens. (See 'Acute promyelocytic leukemia' below and "Molecular biology of acute promyelocytic leukemia".)
High-risk cytogenetics — Children with adverse cytogenetic features account for approximately 15 percent of pediatric AML [6]. Patients with poor-risk cytogenetics include those that lack any favorable changes and harbor any of the following cytogenetic abnormalities: monosomy 7, monosomy 5, deletion of 5q, abnormalities of 3q, t(6;9)(p23;q34), and complex karyotype (defined as three or more cytogenetic abnormalities) [5,10,11]. Children and adolescents harboring these unfavorable features have long-term survival <50 percent, and in some cases <20 percent [5].
For patients with non-Down syndrome acute megakaryoblastic leukemia (AMKL), the cytogenetic abnormalities CBFA2T3-GLIS2, NUP98-KDM5A, and MLL (KMT2A) rearrangements have a poor prognosis compared to patients with normal karyotypes as well as other cytogenetic lesions, and experience an long-term survival of approximately 30 to 40 percent [4]. (See "Prognosis of acute myeloid leukemia", section on 'Karyotype'.)
Translocations involving KMT2A (previously referred to as MLL) at the 11q23 locus are present in 15 to 20 percent of pediatric AML cases. There are many fusion partners of KMT2A and prognosis may vary according to the fusion partner. Rearrangements including t(6;11)(q27;q23), t(10;11)(p11.2;q23.3) and t(10;11)(p12;q23.3) have been associated with a poor prognosis [12,13].
Abnormalities involving 3q, including inv(3)(q21q26.2) and t(3;3)(q21;q26.2), (RPN1-EVI1) are associated with adverse prognosis in pediatric AML [5,13]. In addition, NUP98-NSD1 fusions, which commonly occur with FLT3-ITD mutations, are associated with a poor prognosis in children and adults, and are considered a high-risk lesion [13-16].
Other notable cytogenetic abnormalities — Rearrangements involving KMT2A are most prevalent in young children, especially those <2 years [17]. There are many fusion partners of KMT2A and prognosis may vary according to the fusion partner. The most common rearrangement in pediatric AML involving KMT2A is t(9;11)(p22;q23), which accounts for approximately 50 percent of cases, but this is not associated with adverse outcomes [12]. The t(1;11)(q21;23) rearrangement has been associated with a more favorable outcome relative to other KMT2A fusions [12,13].
Trisomies are common events in pediatric AML, often involving chromosome 8, 19, and 21 and can occur alone or in conjunction with additional karyotypic abnormalities.
Molecular features — Several recurring mutations have been identified in pediatric AML, some of which are predictive of relapse and prognosis. Testing for these mutations is now an integral part of the diagnostic workup and subsequent risk stratification.
High-risk molecular features — Activating mutations in the FLT3 gene are among the most common recurring somatic mutations in AML. Of these, internal tandem duplications of FLT3 (FLT3/ITD) are the most frequent and occur in approximately 10 to 15 percent of pediatric AML [18,19]. The prevalence of FLT3/ITD increases with age, occurring in 15 to 25 percent of adolescents and young adults. Activating loop mutations of FLT3 (FLT3/ALM) that result from point mutations occur at a lower prevalence of approximately 5 to 7 percent and have no prognostic impact [20]. (See "Molecular genetics of acute myeloid leukemia", section on 'FLT3'.)
Patients with mutations involving FLT3/ITD with a high allelic ratio (HAR) of mutant to wild-type FLT3 have a poor prognosis. Although the cutoff used differs by cooperative group, it is generally accepted that an allelic ratio greater than 0.4 to 0.5 is considered HAR and a marker of poor prognosis [20,21]. Patients with HAR FLT3/ITD have a significantly higher risk of being refractory to induction chemotherapy as well as risk of relapse [18]. Children with HAR FLT3/ITD mutations have overall survival rates of approximately 20 to 30 percent with contemporary chemotherapy regimens alone; however, survival improves to approximately 50 to 60 percent when consolidation allogeneic hematopoietic cell transplantation (HCT) is employed [20,21]. (See 'Post-remission therapy' below.)
FLT3 mutations provide a therapeutic target for novel agents. (See 'FLT3 inhibitors' below.)
Low-risk molecular features — In pediatric AML, a low-risk molecular profile includes cases with mutations involving CEBPA and those with NPM1 mutations in the absence of FLT3/ITD:
●Mutations involving CEBPA occur in approximately 5 percent of pediatric AML. Children with CEBPA mutations have a more favorable prognosis with overall survival rates of approximately 70 percent following treatment with chemotherapy alone [22]. (See "Prognosis of acute myeloid leukemia", section on 'CEBPA gene'.)
●Mutations involving NPM1 are present in approximately 8 to 10 percent of pediatric AML. NPM1 mutations often co-occur with FLT3/ITD mutations, so it is important to evaluate for additional mutations [23]. Children with NPM1 mutations that do not harbor the unfavorable FLT3/ITD demonstrate a more favorable prognosis with an estimated survival rate of approximately 70 percent with chemotherapy alone [23]. (See "Prognosis of acute myeloid leukemia", section on 'NPM gene' and "Molecular genetics of acute myeloid leukemia", section on 'NPM1 mutations'.)
Other molecular features — Other recurring mutations, including WT1, KIT, NRAS, and KRAS, have been identified in pediatric AML. Their prognostic significance has not been determined, but their non-random association with additional cytogenetic and molecular aberrations serves as evidence that they likely serve as cooperating mutations in leukemogenesis [24-27]. Additional information about the impact of these gene mutations in adult AML is presented separately. (See "Molecular genetics of acute myeloid leukemia", section on 'Gene mutations' and "Prognosis of acute myeloid leukemia", section on 'Gene mutations'.)
Emerging technologies such as next generation sequencing provide further insights into mechanisms of leukemogenesis; findings include detection of cryptic fusion genes, copy number alternations (CNA; focal gains or losses of genomic regions), loss of heterozygosity (LOH), and distinct immunophenotypes [28-30]. Data regarding these genomic alterations may provide additional prognostic information in pediatric AML and could suggest potential therapeutic strategies in pediatric AML.
Further examination of the clinical impact of these genetic features will be critical to their incorporation into upfront risk stratification and therapeutic allocation.
Response to induction chemotherapy — A significant number of patients do not harbor cytogenetic or molecular abnormalities with prognostic value, and are thus classified as intermediate risk. For this group of patients, the most important prognostic factor is the disease response to induction therapy, including an assessment of measurable residual disease (MRD; also referred to as minimal residual disease) by flow cytometry [31-33]:
●MRD negative – Children in this intermediate-risk group who achieve a remission following the first course of induction (as defined by the absence of MRD detected by flow cytometry) experience a more favorable relapse-free survival of approximately 65 percent [32].
●MRD positive – Children with detectable disease by flow cytometry following induction experience a significantly worse prognosis with a relapse risk of approximately 60 percent [32].
Among children with favorable or unfavorable cytogenetic or molecular features, the role of MRD at the end of induction has not yet been shown to have definitive prognostic significance [32,34]. Detection of MRD by additional methods, such as expression of leukemia-associated genes or disease-specific mutations by polymerase chain reaction (PCR), is somewhat more limited in its use as compared with flow cytometry but can also provide sensitive methods to detect low level of residual leukemia and can inform prognostic and therapeutic decisions [35,36]. (See "Induction therapy for acute myeloid leukemia in medically-fit adults", section on 'Remission assessment'.)
TREATMENT — Chemotherapeutic regimens in children and adolescents most often contain two courses of intensive induction chemotherapy followed by either cytarabine-based consolidation or hematopoietic cell transplantation (HCT). Children and adolescents with AML should be treated in the context of a clinical trial whenever possible. Trials are designed to compare potentially better therapy with that which is currently accepted as standard. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health.
Induction — Standard induction chemotherapy consists of an anthracycline (eg, daunorubicin, idarubicin, or the anthracenedione mitoxantrone) and extended exposure to cytarabine. For children with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes, the US Food and Drug Administration (FDA) approved CPX-351, a liposomal combination of daunorubicin and cytarabine, for children ≥1 year [37]. In some regimens a third drug, such as etoposide or 6-thioguanine, may be included, but the benefit of these additional agents has not yet been proven [38].
In a phase 3 trial for pediatric AML, the antibody-drug conjugate gemtuzumab ozogamicin (GO; which targets CD33), decreased rates of relapse compared to chemotherapy only [7]. GO is approved by the US Food and Drug Administration for the treatment of newly diagnosed AML in adults and for treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients one month and older. When administered as part of induction chemotherapy, GO is generally given as single dose during the first week of therapy and achieve complete remission (CR) rates >70 percent [1,38].
Post-remission therapy — Consolidation with high dose chemotherapy or HCT may be administered after achieving remission. Consolidation chemotherapy using high-dose cytarabine (HiDAC) reduced the rate of relapse in several clinical trials in children [39-41]. The decision to proceed with allogeneic HCT as consolidation must weigh the risk of relapse with the increased risk of mortality and morbidity associated with HCT. Allogeneic HCT is offered to children with high-risk cytogenetics in first CR. Patients with favorable-risk disease features, such as t(8;21) and inv(16), should not be transplanted in first CR. Children with therapy-related AML (ie, after treatment with cytotoxic chemotherapy or radiation therapy for another cancer) have adverse outcomes and should receive consolidation HCT [42].
Both autologous and allogeneic HCT have been investigated in pediatric AML as a strategy to improve survival. No benefit has been demonstrated for autologous HCT compared with nonmyeloablative chemotherapy for children with AML who have achieved remission [43-45]. The role of allogeneic HCT in children and adolescents with AML continues to be an area of active investigation and there is no general consensus among experts. When compared with chemotherapy alone, post-remission allogeneic HCT has been associated with a significantly lower relapse risk in some studies [2,39,46]. However, when applied to all patients, this has not always resulted in improved survival. This discrepancy may be due to the higher treatment-related mortality of allogeneic HCT.
It is generally accepted to offer patients with poor-risk cytogenetics allogeneic HCT as consolidation therapy, although the data supporting this approach are limited. Even with HCT, these children continue to fare poorly. Many studies of patients with poor-risk cytogenetics show no survival benefit using HCT as consolidation therapy compared with chemotherapy alone [47,48]. However, there are published data demonstrating the benefit of HCT for some patients with high-risk disease features in first CR [47,49-51]. As an example, allogeneic HCT in first CR improves survival in children with high allelic burden of FLT3/ITD [21,52,53].
In general, matched sibling donors are a preferred donor source when available; however, unrelated donor sources can yield equivalent outcomes [54]. (See "Donor selection for hematopoietic cell transplantation".)
FLT3 inhibitors — The FLT3-ITD mutation is amenable to targeted agents. The RATIFY trial in adults with FLT3 mutations demonstrated the addition of the FLT3 inhibitor midostaurin to conventional chemotherapy was safe and improved outcomes for patients with FLT3-ITD mutations [55], but its safety and efficacy have not been demonstrated in children. The FLT3 inhibitor sorafenib was associated with decreased relapse and improved survival in children when compared to historical controls not treated with sorafenib [56]. Continued therapy with a FLT3 inhibitor for up to two years after HCT is associated with superior outcomes in adults, and this strategy has also shown to be safe in children [57-60].
Midostaurin is not approved by the US FDA for treatment of children with FLT3 mutated AML.
CNS-directed therapy — Treatment of the central nervous system (CNS) with intrathecal chemotherapy should be given to all children and adolescents with AML, including those without detectable CNS involvement at diagnosis. The intrathecal therapy used varies according to cooperative group protocol. Single agent cytarabine is commonly used, but some protocols use triple therapy consisting of cytarabine, methotrexate, and hydrocortisone. Although cranial irradiation is effective at preventing CNS leukemia, it should not be used prophylactically due to the risks of late effects including cognitive deficits, endocrine deficits, and secondary malignancies [61-63]. The use of HiDAC as systemic therapy, which crosses the blood brain barrier, provides additional CNS-directed therapy. The optimal number of prophylactic intrathecal treatments remains unknown, most regimens and clinical trials provide at least one dose with each course of therapy.
CNS involvement occurs in 5 to 10 percent of children with AML at diagnosis [64]. Risk factors associated with CNS involvement include age <2 years, high white blood cell (WBC) count, hepatosplenomegaly, t(8;21), inv(16), or t(16;16) [64,65]. Patients with CNS involvement require augmented CNS-directed therapy. CNS positivity at diagnosis is not an adverse prognostic factor for children with AML, and with intensified CNS-directed therapy does not affect overall survival [64]. Frequent intrathecal chemotherapy combined with intensive systemic chemotherapy, including HiDAC, may be as effective as cranial irradiation in patients with CNS involvement and radiation may not be necessary [64,65].
Myeloid sarcomas — Myeloid sarcoma (MS), also known as chloromas, refers to deposits of myeloid blasts outside the bone marrow that may cause destruction or compression in normal tissue. Sites of MS most commonly include the CNS, skin, orbit, and bone. The incidence of MS in pediatric AML is approximately 10 percent and is more common in patients with the following features [66,67]:
●Younger age
●High white blood cell count at diagnosis
●t(8;21)
●French-American-British (FAB) M4 and M5 morphology
Some studies in adults have demonstrated high relapse rates and lower survival in patients with MS. In children, the prognostic impact of MS appears to depend upon the site of involvement [64,66,67]. Pediatric patients with MS involving the CNS or orbit have demonstrated improved survival compared with those without CNS/orbit involvement and patients without MS. In contrast, children with chloromatous skin involvement have higher rates of relapse. Extramedullary relapses are more common among those with extramedullary disease at diagnosis. Focal radiation may provide symptomatic benefit, however, it does not appear to offer any additional progression-free or overall survival benefit to chemotherapy in patients with MS [66,68].
Acute promyelocytic leukemia — Acute promyelocytic leukemia (APL) is a rare subtype of AML that is characterized by maturation arrest at the promyelocyte stage and the classic chromosomal translocation t(15;17)(q22;q21) [9]. (See "Molecular biology of acute promyelocytic leukemia".)
APL is risk stratified based on the presenting WBC count, with patients presenting with a WBC <10x109/L (<10,000/microL) classified as standard risk and those with a WBC >10 x 109/L classified as high risk [69]. Patients with high WBC counts experience higher rates of relapse and are especially susceptible to early mortality due to coagulopathy (ie, disseminated intravascular coagulation [DIC]). Many patients with APL present with DIC that requires urgent and aggressive management. All-trans retinoic acid (ATRA) should be started quickly when APL is suspected [70].
ATRA, which targets the PML-RARA fusion protein and induces differentiation of the blasts, is a critical component of successful treatment of APL [71]. Anthracyclines have been used historically as a mainstay of treatment in APL, and when combined with ATRA and arsenic trioxide (ATO), result in excellent survival [72-75]. Clinical trials in adults have demonstrated equivalent survival in standard-risk patients when treated with ATRA and ATO alone, while anthracycline is utilized in induction for high-risk patients [76,77]. Retrospective studies in children have shown a regimen of ATRA plus ATO for standard risk APL is well tolerated and results in excellent outcomes, similar to adults [78]. The management of APL in adults is presented in detail separately. (See "Initial treatment of acute promyelocytic leukemia in adults".)
DOWN SYNDROME AND AML — Down syndrome (DS) is well recognized as a cancer predisposition syndrome. Children with DS have 10 to 20 times greater risk of developing AML compared with children without DS. Infants with DS can also develop the transient myeloproliferative disorder (TMD) of DS, also known as transient abnormal myelopoiesis (TAM), which occurs at a prevalence of approximately 10 percent. TMD is a clonal myeloproliferative disorder that presents with peripheral leukocytosis and the appearance of megakaryoblasts in the peripheral blood that are identical to those seen in acute megakaryoblastic leukemia (AMKL). Complications include pericardial and pleural effusions, coagulopathy, hydrops fetalis, hepatic dysfunction, and hepatic fibrosis [79-81]. TMD is discussed in more detail separately. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)
For the majority of infants of who develop TMD, the disease resolves spontaneously without any treatment and over 50 percent of infants experience resolution by six months of age [81]. Approximately 20 to 25 percent of infants with TMD require treatment with chemotherapy, which is often indicated due to respiratory compromise, liver dysfunction, or hyperviscosity associated with hyperleukocytosis [81]. Infants who are diagnosed with TMD are followed with frequent complete blood counts with differential in the first five years of life as approximately 20 to 25 percent of infants can develop AML, even after the resolution of TMD [7,79]. Children with longer time to resolution of TAM may have a higher risk of subsequent AML, and most cases of AML in children with DS present by four years of age [81].
AML in children with DS has unique biologic characteristics that greatly influence therapy and prognosis. Children with DS commonly develop AMKL, a subtype of AML that is rare in children without DS [82,83]. The additional chromosome 21 is recognized as important factor in leukemia predisposition. A key event in the leukemogenesis of DS-AML, as well as TMD, is the acquisition of mutations in the GATA1 gene, which is important in hematopoietic development [84,85].
Overall, children with DS have superior overall survival when compared with children with AML who do not have DS. Leukemic cells of DS-AML exhibit increased sensitivity to cytarabine and daunorubicin [86,87], and children with DS-AML can experience excellent outcomes without the intensive therapy that is needed to achieve cure in pediatric AML [38,88-91]. A multicenter trial of 204 patients with DS-AML who received high dose cytarabine early in the course of treatment and a reduced cumulative dose of daunorubicin resulted in five-year event free survival and overall survival of 90 and 93 percent, respectively [92].
Importantly, children with DS have higher rates complications from intensive chemotherapy, namely infection and cardiotoxicity [83,93]. It is essential that children with DS who develop AML are treated with DS-specific therapy as they cannot tolerate the toxic effects of the intensive pediatric AML regimens. Chemotherapy regimens using a backbone of cytarabine and an anthracycline are effective at achieving remission and can cure the majority of patients, especially when toxicity is minimized [88,94,95]. A multicenter trial of 170 children with DS-AML demonstrated that reduction of cumulative etoposide, less intrathecal CNS prophylaxis, and elimination of maintenance therapy did not impact survival with five-year event-free survival of 87 percent and overall survival of 89 percent [96]. Modern clinical trials have focused on increased utilization of cytarabine, lower doses of anthracyclines, as well as enhanced supportive care.
Unfortunately, children with DS who achieve inadequate response or relapse following therapy have very poor outcomes and are not good candidates for conventional intensity allogeneic hematopoietic cell transplantation (HCT) [97]. Children with DS who receive HCT for AML have very poor outcomes that are attributed to high treatment-related morbidity and incidence of relapse [98].
SUPPORTIVE CARE — Improvements in supportive care have been essential to the improved outcomes observed in pediatric AML over the past several decades. Children and adolescents with AML are at risk for significant morbidity and mortality both from their disease and the direct effects of curative therapy.
Hyperleukocytosis — Hyperleukocytosis is defined as a white blood cell (WBC) count of >100,000/microL (>100 x 109/L) and is a risk factor for significant complications including leukostasis, disseminated intravascular coagulation (DIC), and tumor lysis syndrome (TLS). The risk of serious complications and mortality from these issues is highest at the time of diagnosis and within the days following the initiation of therapy [99]. It is important to recognize that the WBC count is a somewhat arbitrary threshold and does not always predict the presence of complications. Compared with acute lymphoblastic leukemia (ALL), complications of hyperleukocytosis are more common and can occur at comparatively lower WBC counts in AML [100]. In pediatric AML, higher WBC counts are more common in patients presenting with FLT3/ITD, MLL rearrangements, FAB M4 and M5 phenotypes, and the CBF lesions [20,99,101].
●Leukostasis – Hyperleukocytosis may lead to tissue damage from blast infiltration and leukostasis, resulting in hemorrhagic and thromboembolic events. The clinical presentation of leukostasis varies depending on the affected organs. Patients with lung involvement may present with dyspnea, hypoxemia, or respiratory failure while neurologic involvement may manifest as somnolence, coma, or focal neurologic deficits. Leukostasis is an oncologic emergency and can be life threatening, especially the pulmonary and neurologic complications [102]. Although leukapheresis or exchange transfusion can effectively lower the WBC count temporarily, these procedures pose significant risk, are temporary, and can exacerbate thrombocytopenia and risk of DIC [103]. Due to the risks and limitations of these procedures, they are not generally recommended for pediatric AML patients without symptoms of leukostasis [104,105]. The most effective means at achieving reduction in WBC is prompt diagnosis and initiation of chemotherapy [102].
●Tumor lysis syndrome – Supportive management should include hyperhydration to reduce risk of tumor lysis and decrease blood viscosity. TLS may manifest as hyperphosphatemia, hypocalcemia (caused by precipitation of calcium phosphate), hyperuricemia, hyperkalemia, and acute renal failure. Rapid leukemic cell lysis after chemotherapy can cause over-production and over-excretion of uric acid. The precipitation of uric acid in the tubules can lead to oliguric or anuric renal failure known as uric acid nephropathy. Administration of prophylactic medications to prevent complications of TLS, such as allopurinol or rasburicase, and careful monitoring of renal function is essential. (See "Tumor lysis syndrome: Prevention and treatment".)
●Disseminated intravascular coagulation – Acute DIC occurs most commonly in patients presenting with hyperleukocytosis, monocytic subtypes (FAB M5), or with acute promyelocytic leukemia (APL). If APL is suspected, all-trans retinoic acid (ATRA) should be started immediately before the diagnosis is confirmed as it is the most important treatment of DIC in this population. Supportive care of patients with AML-associated DIC should include standard management with appropriate blood products (eg, platelets and coagulation factors), which is essential to minimize bleeding risk. (See "Disseminated intravascular coagulation in infants and children".)
Infectious complications — The intensity of the treatment required to cure AML carries a significant risk of severe infections with bacteria, viruses, and fungi. The infectious risk is due, in part, to alterations in mucosal barriers and the prolonged absence of neutrophils. Adolescents and young adults may be at higher risk for treatment-related toxicity compared with younger children [106,107].
Prompt antibiotic administration is critical for any child with fever who is undergoing treatment for AML; management of fever in this setting is discussed separately. (See "Fever in children with chemotherapy-induced neutropenia".)
Bacterial infections — Bacteremia is a leading cause of morbidity and mortality in children who are treated with intensive chemotherapy for AML, and viridans group streptococci and gram-negative bacteria are common pathogens in this setting. Antibiotic prophylaxis can reduce the risk of bacteremia during intensive chemotherapy treatment, but there is no demonstrated role for prophylactic administration of granulocyte colony-stimulating factor (G-CSF) [108-110].
The role of antibiotic prophylaxis in children undergoing AML remission induction therapy is controversial. While we do not routinely treat with antibiotic prophylaxis, some experts do suggest prophylactic quinolones. The reasoning behind our approach is that although levofloxacin prophylaxis can decrease the incidence of bacteremia and febrile neutropenia in this setting, it has not been shown to reduce sepsis or improve survival; the benefits must be balanced against the potential for toxicity and/or complications, and should be considered from the perspective of institutional resistance patterns and the potential for emergence of antibiotic resistance. We favor more data to support a benefit for critical outcomes such as sepsis or survival before routinely suggesting this approach. However, it is worth noting that fluoroquinolone prophylaxis is suggested for adults who are at high risk for neutropenic fever. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults", section on 'Indications'.)
A multicenter trial randomly assigned 195 children (age 6 months to 21 years) who were undergoing two cycles of intensive chemotherapy for AML or relapsed ALL to levofloxacin prophylaxis versus no prophylaxis [108]. Compared with no prophylaxis, the likelihood of bacteremia in children receiving levofloxacin prophylaxis was reduced (21.9 versus 43.4 percent, respectively; risk difference, 21.6 percent; 95% CI 8.8-34.4 percent), and the study was terminated early when a planned interim analysis demonstrated the efficacy of levofloxacin. Levofloxacin prophylaxis was also associated with fewer episodes of fever and neutropenia (71.2 versus 82.1 percent), but there were no differences between the levofloxacin and placebo groups in the other secondary outcomes (ie, severe infections, invasive fungal disease, Clostridioides [formerly Clostridium] difficile-associated diarrhea, musculoskeletal toxic effects). Notably, the reduction of bacteremia for children with AML was modest (23.4 versus 29.7 percent), and there was no benefit in a cohort of children undergoing allogeneic hematopoietic cell transplantation (HCT); the effect was most pronounced in children with relapsed ALL. Viridans group streptococci were the most commonly cultured organisms, and in the small sample of isolates available for sensitivity testing, all five isolates from children receiving prophylaxis were resistant to levofloxacin, whereas all eight isolates from the untreated patients were sensitive.
Viridans group streptococci can cause severe sepsis and viridans streptococcal shock syndrome (SVS), resulting in hemodynamic instability and acute respiratory distress syndrome. The risk of infection with viridans group streptococci is more pronounced in patients treated with high dose cytarabine (HiDAC) and those with prolonged neutropenia [111]. Among children treated for AML, as many as 25 percent develop SVS [112]. Prompt recognition of the potential for SVS is critical as rapid progression can be fatal and appropriate intravenous antibiotics should be started immediately [113]. Details regarding the choice of antibiotic therapy are presented separately. (See "Fever in children with chemotherapy-induced neutropenia".)
Fungal infections — Severe fungal infections, including those caused by yeasts (eg, Candida spp) and invasive molds (eg, Aspergillus spp) pose a significant risk throughout AML therapy and for those undergoing allogeneic HCT [114]. Antifungal prophylaxis is effective at reducing invasive fungal infections and should be incorporated into management of children and adolescents receiving therapy for AML [110,115]. New or prolonged fevers in the setting of neutropenia should prompt suspicion of fungal infection, and empiric antifungal therapy should be administered immediately for presumed or documented fungal infections; treatment should not be delayed for completion of the diagnostic workup [116-118]. (See "Fever in children with chemotherapy-induced neutropenia".)
Antifungals used for prophylaxis include fluconazole, which has activity against Candida spp, [119] and voriconazole, posaconazole, and itraconazole, which have activity against both Candida spp and molds, such as Aspergillus spp [120-123]. The choice of regimen depends upon the most likely pathogen, and specific practices vary between centers. Consultation with Infectious Disease specialists should be considered in cases of presumed or documented infections. (See "Treatment and prevention of invasive aspergillosis".)
Initial evaluation of new or prolonged fevers in the setting of neutropenia should include computed tomography (CT) of the chest, abdomen, pelvis, and sinuses [124]. If a patient has additional symptoms that involve extremities or the central nervous system (CNS), appropriate imaging and diagnostic testing, including examination of the cerebrospinal fluid (CSF), should be obtained. Among patients with radiographic lung findings suspicious for fungal infection, additional diagnostic testing may include bronchial alveolar lavage or biopsy of suspicious lesions [118].
RELAPSED LEUKEMIA — Approximately 30 percent of children with AML will experience relapse. In general, the prognosis for these children is poor with about one-third of children being cured. Patients with core binding factor AML and other favorable molecular lesions are more likely to achieve long-term survival. Survival is especially poor for patients with high-risk disease features or those who have previously received allogeneic hematopoietic cell transplantation (HCT). The time to relapse is an important prognostic factor, and survival is less than 20 percent for patients relapsing within one year of achieving complete remission (CR) [125].
Re-induction regimens for children and adolescents with relapsed AML vary, but commonly include high-dose cytarabine (HiDAC) with or without an anthracycline. The use of an anthracycline depends on cardiac function at relapse and the cumulative anthracycline dose with initial therapy. Regimens often combine HiDAC with other agents such as fludarabine and clofarabine, and anthracyclines when appropriate [126-128]. Gemtuzumab ozogamicin (GO) has also shown responses in relapsed CD33 positive AML, either as a single agent or in combination with additional chemotherapy agents [129,130]. GO is approved by the US Food and Drug Administration for treatment of relapsed AML in children, as a single agent.
Achievement of a second CR is the most important prognostic factor in long-term survival, and patients who have no evidence of measurable residual disease (MRD; also referred to as minimal residual disease) following second-line therapy and prior to HCT have the best outcomes [126]. Consolidation HCT in CR is recommended for patients that relapse. Early phase clinical trials with novel agents should also be considered for all children and adolescents who relapse.
LATE EFFECTS — Advances in the treatment of childhood and adolescent AML have resulted in an increasing number of cancer survivors and have brought important attention to the late effects of chemotherapy and allogeneic HCT. Although information regarding late effects is not as robust as for acute lymphoblastic leukemia (ALL), potential late adverse effects include late onset cardiotoxicity, central nervous system (CNS) impairment, decreased linear growth, infertility, cataracts, and an increased incidence of secondary cancers as well as an overall decreased health status due to such factors as neurocognitive dysfunction, depression, fatigue, and anxiety. (See "Assuring quality of care for cancer survivors: The survivorship care plan" and "Overview of cancer survivorship in adolescents and young adults".)
Anthracyclines remain very effective agents in AML but carry a risk of early as well as late onset cardiotoxicity, which in the most severe cases results in heart failure. The cumulative dose of anthracyclines is the most important risk factor for late cardiac effects. Although there is no dose of anthracyclines that is recognized to be safe, cumulative anthracycline doses of >300 mg/m2 result in significantly higher rates of late cardiac compromise and this risk rises even more steeply in excess of 400 mg/m2 [131,132]. Current United States and European treatment protocols for AML utilize between 300 to 440 mg/m2 cumulative anthracycline dosing and estimated incidences of late cardiac effects are 3 to 5 percent [133,134]. Children and adolescents treated for AML should receive long-term follow-up with routine cardiac monitoring.
Survivors of childhood AML are at risk for secondary neoplasms, mainly solid tumors, and long-term follow-up data demonstrate a prevalence of approximately 1.7 percent [135]. This risk is increased in patients who receive radiation, which is often a part of HCT conditioning [136].
The intensity of therapy for AML, especially radiation therapy for HCT, also puts survivors at risk for endocrine dysfunction, with the thyroid and gonadal systems the most affected [135-137]. Children who receive total body irradiation or cranial irradiation are also at risk for growth defects and neurocognitive dysfunction; this is more pronounced in very young children who receive radiation [138].
The occurrence of specific complications depends on the patient's age and the type and intensity of therapy with which they were treated. Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group, and are available at www.survivorshipguidelines.org.
FUTURE DIRECTIONS — Children and adolescents with AML should be treated in the context of a clinical trial whenever possible. Trials are designed to compare potentially better therapy with that which is currently accepted as standard. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health.
New technologies, such as next-generation sequencing, that can more deeply interrogate AML at the genomic and epigenomic level have the potential to identify novel biomarkers that can enhance risk stratification and potential therapeutic targets. To date, increased understanding of AML at the molecular level has provided insights into molecular lesions that can be targeted for therapy in pediatric AML. The FLT3/ITD mutation is one of the first genomic lesions in AML to be directly targeted with FLT3 inhibitors and demonstrated efficacy in adults and children with this mutation. As an example, the potent FLT3 inhibitor gilteritinib is active in adults with relapsed FLT3 mutant AML, and trials are underway to incorporate these agents into regimens for children [139]. Other mutations (eg, KIT, IDH1/2) that are amenable to therapeutic targeting are also being evaluated for children.
Therapeutic strategies designed to target AML at the molecular level, including epigenetic modifiers and targeted inhibitors, are active areas of investigation in pediatric AML [140]. Liposomal daunorubicin-cytarabine (CPX-351) has efficacy in adults with AML with unfavorable features (eg, therapy-related AML) and preliminary reports suggest efficacy in pediatric studies [141-143]. CD33 is expressed on the majority of pediatric patients with AML, and its high expression has also been associated with poor prognostic features [144-146]. Additional antibody-drug conjugates directed against CD33, as well as alternative antigens, such as CD123, and additional strategies including chimeric antigen receptor T cells (CAR-T), novel T cell engagers (eg, dual affinity targeting receptors), and natural killer (NK) cell therapy are currently being investigated in AML [147-153]. A number of clinical trials investigating these strategies are currently enrolling patients with relapsed and refractory AML, including children.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute myeloid leukemia".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Leukemia in children (The Basics)")
●Basic topic (See "Patient education: Acute myeloid leukemia (AML) (The Basics)".)
SUMMARY AND RECOMMENDATIONS
●Acute leukemia is the most common cancer in children. Acute lymphoblastic leukemia (ALL) accounts for the vast majority of pediatric acute leukemia. In contrast, acute myeloid leukemia (AML) is much less common in the pediatric population, representing approximately 15 percent. While survival rates have improved over the past several decades, survival in children with AML is lower than that of children with ALL.
●Children with AML commonly present with fever, malaise, musculoskeletal pains, lymphadenopathy, hepatosplenomegaly, and bleeding. Blood work usually demonstrates anemia and thrombocytopenia. The white blood cell count can be decreased, normal, or increased. Less common complications that may require urgent intervention include disseminated intravascular coagulation (DIC), signs and symptoms related to central nervous system involvement, hyperleukocytosis, and tumor lysis syndrome. (See 'Clinical presentation' above.)
●The diagnostic evaluation of children and adolescents with AML should include an evaluation for these potential complications along with a pathologic review of the morphology, immunophenotype, and genetic features. These studies both distinguish AML from ALL and other entities and provide information needed for risk stratification. (See 'Diagnostic evaluation' above and 'Pathologic features' above.)
●Risk stratification incorporates cytogenetic and molecular features, genetic profiles, and response to induction chemotherapy. Treatment on research protocols is recommended as such protocols have helped to standardize treatment, improve survival rates, and decrease complications of therapy. Chemotherapeutic regimens in children and adolescents most often contain two courses of intensive induction chemotherapy followed by either cytarabine-based consolidation or allogeneic hematopoietic cell transplantation (HCT). Central nervous system prophylaxis is a standard component of therapy. (See 'Treatment' above.)
●Patients undergoing AML therapy experience significant myelosuppression and have a high risk of infectious complications, but we suggest not routinely administering prophylactic antibiotics for children and adolescents receiving intensive chemotherapy for AML (Grade 2B). Fluoroquinolone prophylaxis can reduce the incidence of bacteremia and febrile neutropenia, but has not been shown to reduce sepsis or survival; these benefits must be balanced against the potential for toxicity, complications, and emergence of antibiotic resistance. Some experts do suggest routine prophylaxis with levofloxacin in this setting. (See 'Bacterial infections' above.)
●New or prolonged fevers in the setting of neutropenia should prompt suspicion of fungal infection, and empiric antifungal therapy should be administered immediately for presumed or documented fungal infections. Specific practices for antifungal prophylaxis and treatment vary between centers, and consultation with Infectious Disease specialists should be considered in cases of presumed or documented infections. (See 'Fungal infections' above.)
●Although cure rates for children and adolescents with AML have approached 70 percent, outcomes for children with adverse prognostic biologic features and refractory or relapsed disease remains poor. Novel therapies for the high-risk patients are needed. (See 'Relapsed leukemia' above and 'Risk stratification' above.)
●Children and adolescents treated for AML should also be monitored closely for long-term complications of treatment regimens and require regular follow-up throughout their lives. (See 'Supportive care' above and 'Late effects' above.)
●Children with Down syndrome (DS) have an increased risk for developing AML. AML in children with DS has unique biologic characteristics that greatly influence prognosis and therapy. (See 'Down syndrome and AML' above.)
